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Bisphosphonates for Complex Regional Pain Syndrome?

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If you have Complex Regional Pain Syndrome and you have severe pain that has failed all remedies, you may wish to consider bisphosphonate infusions for pain relief. This area needs more research – there is almost none, only three or four small publications on pamidronate for chronic noncancer pain that I posted here.

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Those posts on bisphosphonates in the last two weeks have developed the background to the use of bisphonates for chronic noncancer pain. This is not everyday medicine for pain control, but it is common for certain cancers and for osteoporosis.

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There is a science behind this choice. There is a strong rationale, it makes sense, but this is serious therapy.

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We do not know if it will work or how many may benefit.

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To my knowledge, it has not been done outside of those three or four very small studies. No one is offering this therapy for CRPS. But we all see patients who have tried and failed every known therapy that exists, and pain has taken their lives.

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Here we review these specific points:

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-Safety

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-How soon you can consider pregnancy after treatment?

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-Side effects with the infusion

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-Calcium supplements you need to take

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Information has been taken from the award winning website of Susan Ott, Professor of Medicine at University of Washington and an expert on bisphosphonates and metabolic bone disease. Her teaching goes beyond what can be gleaned from publications, and thankfully spans the depth of the field. It is a concise encyclopedia of bisphosphonates for physicians and patients. Apologies to Professor Ott, I have quoted her work liberally.

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SAFETY

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“Unlike most medications, bisphosphonates remain in the body for decades. These drugs are not metabolized….The amount of drug within the bone will accumulate with use. There is no known method of removing the medication from the bones. The duration of physiological effect is still unknown.”

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Further, she notes the reduced risk of fracture is not closely linked to the increase in bone density. Fracture rate was higher with increased density. E.g., hip fracture decreased with 2.5 mg/d risedronate relative to placebo, but 5.0 mg/d was same as placebo.

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The issue:

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As bone mineralization increases, bone becomes more brittle.

Brittle bone may be more susceptible to fracture.

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PREGNANCY

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It is recommended that you not become pregnant while bisphosphonate is in your bones.

It is contraindicated in women who are pregnant or planning pregnancy.

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Her advice: wait at least one year after stopping the medication to try getting pregnant. The drugs are still excreted in the urine 8 years after stopping.

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Women who are pregnant should not take bisphosphonates. If women are already taking a bisphosphonate and want to become pregnant, it is not clear how long they should wait [my emphasis]. Until more information is available, I suggest waiting at least one year after stopping the medication to try getting pregnant. If a woman is taking a bisphosphonate and inadvertantly gets pregnant and wants to continue the pregnancy, she should be carefully followed, with measurements of calcium and optimal vitamin D levels. Calcitonin is a safe drug to use during pregnancy if bone loss is a concern.

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See below, for more details on toxicity studies in pregnancy.

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SIDE EFFECTS AFTER THE INFUSION

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The day after the infusion it is common to have a fever. Some patients feel like they are getting the flu and feel aching and tired. This usually lasts only one or two days. You may have pain in the bone, especially if you have Paget’s disease or fibrous dysplasia. Other complications are not common, and include a transient decrease in the white blood cell count or blood calcium. The infusion site may become sore or infected. Rare side effects are inflammation of the eyes, kidney damage, or problems with the bones underneath the teeth.

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To be safe, the following blood tests should be normal before giving pamidronate: calcium (greater than 9.0 mg/dl) creatinine, white blood cell count, vitamin D (at least 20 ng/ml). It should not be given during an active infection.

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More detailed studies of blood that I do will also include post infusion study of urine for urinary cross-linked N-terminal telopeptides of type I collagen (NTX).

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CALCIUM SUPPLEMENTS – WHICH ONES?

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Patients need to be sure to get adequate calcium and vitamin D after pamidronate infusions.

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Professor Ott recommends specific calcium supplements— not all are equal. “Many brands do not dissolve in the intestines, so the calcium is not absorbed into the bloodstream.”

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She lists these brands to take, with photos and cost in order of price:

Effects of bisphosphonates during pregnancy. Bisphosphonates should be avoided during pregnancy. Refer to her summary for details of animal toxicity studies and human studies.

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There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As it has been shown that Aredia can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy.

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Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

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Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aredia is administered to a nursing woman.

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The material on this site is for informational purposes only, and is not a substitute for

Bisphosphonates have been used for treatment of pain.

I have reviewed a few studies on pamidronate infusions for pain, below.

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Based on these small studies, there is a growing rationale for use of I.V. pamidronate in the setting of selected chronic intractable pain syndromes.

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Have you received IV Pamidronate or Reclast or any bisphosphonate

for treatment of pain caused by any condition?

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Bisphosphonates are effective for reducing bone loss and, separate from that mechanism, they have been used to reduce pain in persons with various conditions including Complex Regional Pain Syndrome, ankylosing spondylitis, rheumatoid arthritis, chronic back pain, and other conditions.

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If you have any experience with bisphosphonates even if for osteoporosis, please comment below. Do you know which academic centers are giving IV bisphosphonates for pain?

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The mechanism of pain relief is not clear and there are no standardized protocols for the use of bisphosphonates for pain, but relief of pain is believed to be separate from mechanisms related to bone.

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Many patients have no other options for treatment. There are no large randomized controlled studies – where is NIH funding for pain?

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Many medical treatments do not work for some patients with Complex Regional Pain Syndrome or for chronic low back pain. When all else has failed, pamidronate may be given IV, often in a series of infusions that take up to four hours. There may be some flu-like symptoms for 1 to 3 days after.

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For reasons unknown to us, Complex Regional Pain Syndrome is often associated with bone loss in the area of pain. It is more marked and prolonged than in immobilized trauma patients.

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What dose should be used, how often should it be given? Few studies have been published.

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MEDICATIONS for OSTEOPOROSIS

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Bisphosphonate therapy is commonly used for diseases of bone such as osteoporosis or Paget’s Disease, multiple myeloma, bone metastasis, osteogenesis imperfecta, fibrous dysplasia. For example alendronate (Fosamax) or residronate (Actonel) tablets, pamidronate infusions, or others. Zoledronic acid (Reclast) is given IV, usually only once each year. One form of ibandronate (Boniva) is also given IV, usually every 3 months.

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Other medications that are not bisphosphonates are used for osteoporosis such as calcitonin-salmon (Miacalcin) SC or IM injections, Forteo (rhPTH ) SC injections, or estrogen.

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MECHANISM of BISPHOSPHONATES

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Bisphosphonates slow the rate of bone loss, they do not actually build bone. Bone requires a balance of osteoblasts that form new bone, and osteoclasts that resorb bone. Osteoporosis occurs with age and especially with loss of estrogen that dramatically increases loss of bone. Other factors that lead to bone loss are lack of exercise, hormonal, nutritional and genetic predispositions.

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RISKS of OSTEOPOROSIS

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Some of the worst pain I have seen in my career is pain due to fractures of fragile osteoporotic bones. It may be impossible to treat. With osteoporosis, you may simply roll over in bed and 7 rib fractures occur. One woman developed hundreds of fractures throughout her pelvis and was bedridden for years after a very minor incident. Bone stimulators did not help and she could not walk or stand without help. Years later there was a 1-1/2 inch gap between the fractures in her pelvis and of course being inactive and bedridden can only make osteoporosis worse.

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RISK of MEDICATION for OSTEOPOROSIS

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Osteoporosis is more dangerous by far than any medication used to treat it. As with any drug, the benefit must outweigh side effects. Bisphosphonates increase bone thickness and reduce risk of fractures. Osteoporosis medications causes less than 1% risk of bone fractures. Fractures from the medications may be seen in the midshaft of the femur which is the mid thigh; and they may cause osteonecrosis of the TMJ, the jaw bone. Serious problems with bone healing after dental surgery may occur in those who take bisphosphonates. But the risk of osteoporosis is far greater than this small risk.

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Non-bisphosphonates also have dangers: Calcitonin may increase risk of cancer. PTH is the only one that can actually build bone – an anabolic agent that induces bone formation, not just prevent resorption of bone, but abrupt termination leads to rapid loss of bone density. Estrogen increases risk of clotting, thromboembolism that is a risk for stroke.

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Neridronate is a new bisphosphonate available so far only in Europe the last few years. They are making claims that a series of neridronate infusions can reduce pain 100% in persons with Complex Regional Pain Syndrome. That seems highly unlikely: 100% effective? Really? Oh, and so far no reports of necrosis of bone. But it has not been available as long as pamidronate, so it may be years before we get a better assessment of this drug that is confirmed by other laboratories.

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PUBLICATIONS

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Dr. Pappagallo published three of the studies below. He is one of the foremost scientist-pain specialists in the world.

[Pain was decreased by > 4 points. They showed no relationship between bone density and analgesic response, but did find a relationship between PTH, vitamin D status and pain response.]

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Bisphosphonates are known to have significant analgesic activity in addition to their well-characterized role in inhibiting bone resorption. For example, pamidronate (Aredia®, Novartis), an aminobisphosphonate, demonstrates clinically significant pain relief when administered intravenously for the treatment of Paget’s disease, metastatic breast cancer and osteolytic lesions of multiple myeloma [5], [24], [51]. In addition, i.v. pamidronate has been shown to have analgesic activity in a wide variety of painful conditions, including complex regional pain syndrome [12], [44], [53], fibrous dysplasia [10], recurrent multifocal osteomyelitis [22], [35], ankylosing spondylitis [33], rheumatoid arthritis [31], and others (for review, see [49]). The mechanism(s) of this analgesic effect is not fully known, but antinociceptive effects of pamidronate and other bisphosphonates have been reported in animal models of pain [7], [8], [25], [52]. Inhibition of osteoclast proton secretion and other cellular and molecular mechanisms may contribute to the analgesic effect [37], [54].

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The molecular mechanisms of pamidronate’s analgesic effects are not fully understood. Bisphosphonates are known to inhibit the activity and/or cause apoptosis of osteoclasts [20], [46], which remodel bone by creating an acidic microenvironment via the release of protons through vacuolar H+-ATPase [6], [45]. Osteoclast-induced high concentrations of protons may activate acid-sensing ion channels and transient receptor potential vanilloid type 1 channels expressed by small nerve fibers involved in pain signal transmission [37], [42], [54]. Osteoclasts appear to have a role in inflammatory pain adjacent to bone and in the hyperalgesia observed in type IX collagen-deficient mice [2], [37]. Of interest, inhibition of osteoclasts by bisphosphonates in a rat model of degenerative joint disease has recently been found to prevent subchondral bone resorption and cartilage loss, and decrease pain [50]. Clinical findings may also suggest a role for subchondral bone changes in the early development of painful osteoarthritis [13], [36]. Furthermore, the anatomical core structure of the spine is made of bone tissue, and immunohistochemical studies have revealed the presence of a widespread network of peptidergic small sensory fibers throughout the bone marrow, mineralized bone, and periosteum [28], [32]. Thus it is conceivable that: a) nonspecific low back pain (associated with degenerative disk disease or spondylotic disease as in our study population) may be related to sensitization of bone nociceptors, plausibly in the context of subchondral bone resorption (eg, at the vertebral endplates and/or facet joints) and b) inhibition of subchondral osteoclasts (and possibly of other phagocytic or inflammatory bone resident cells) by i.v. pamidronate might be clinically relevant to the treatment of CLBP.

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The responder rate for pamidronate 180 mg increased from 50% at 24 hours after the second infusion to 100% at month 2; the 100% responder rate was maintained at all subsequent time points. [There were 7 patients in each group of this small study.]

(Fig. 3) illustrates that all subjects receiving 180 mg pamidronate had at least 50% pain relief at both 3 and 6 months postinfusion, and approximately 80% of subjects receiving 180 mg pamidronate had 100% pain relief at 6 months.

The efficacy of pamidronate in patients with spondyloarthropathies; synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome; hypertrophic osteoarthropathy; osteoporotic vertebral fractures; chronic back pain due to disk disease or spinal stenosis; Charcot arthropathy; transient osteoporosis; and complex regional pain syndrome-I, has been demonstrated in more than 40 reports, the majority of which, however, were not controlled studies. In some of reviewed conditions, aside from providing analgesic relief, pamidronate may also have disease-modifying properties. While used in different doses in a variety of rheumatic disorders, pamidronate was generally reported to be well tolerated with an overall good safety profile. Pamidronate may represent an effective and safe choice for a spectrum of rheumatic patients, suffering from intractable musculoskeletal pain, unresponsive to traditionally recommended therapies. Large randomized, controlled studies examining the efficacy of pamidronate in the rheumatic conditions are urgently needed.

Pamidronate 60 mg iv was given only one time to 14 patients, 13 placebo controls.

Overall improvements in pain score, patient’s global assessment of disease severity score, and physical function (SF-36) score were noted in the pamidronate group at 3 months, and improvements in role physical (SF-36) score were noted at 1 and 3 months. There was variability in pamidronate response among individuals. CONCLUSIONS: Pamidronate may be a useful treatment option in the management of patients with CRPS Type I. Although treatment response was variable, the majority of patients improved.

[They] reviewed the charts of 25 patients who had experienced disabling spinal pain for several years, and whom we treated with [iv] pamidronate. None had a history of osteoporotic vertebral fractures or metastatic disease. Pain rating scores decreased in 91% of patients: on a 0–10 numeric rating scale, the mean pain change was 3.6 points and mean percentage change was 41% (P <0.0001).